Novel 5{40 ,6{40 -dihydro-2h-pyran-4{40 -yl prostaglandin ethers

ABSTRACT

Novel 5&#39;&#39;,6&#39;&#39;-dihydro-2H-pyran-4&#39;&#39;-yl prostaglandin ether compounds of the formula WHEREIN R1 is hydrogen or lower alkyl; R2 and R3 are hydrogen when Y is a single bond and R2 R3 are absent when Y is a double bond; R5 is hydrogen or WHEN X is a double bond; and WHEN X is a single bond; WHEN X is a double bond and WHEN X is a single bond; Z1 is a cis or trans -CH CH- or CH2CH2-; Z2 is trans -CH CH- or -CH2CH2-; n is 1 to 5; m is 0 to 5; and the non-toxic salts. The novel compounds possess pharmacological properties as modifiers of smooth muscle activity, gastric secretion, blood pressure, lipolysis and the reproductive system. The compounds also induce labor and menses and they can be used for the relief of asthma and nasal congestion and as platelet anti-aggregation agents.

United States Patent [191 W einshenker et al.

[ NOVEL 5 ',6 '-DIHYDRO-2H-PYRAN-4-YL PROSTAGLANDIN ETHERS [75]Inventors: Ned M. Weinshenker, Sunnyvale, Calif.; Niels H. Andersen,Seattle, Wash.

[73] Assignee: Alza Corporation, Palo Alto, Calif.

[22] Filed: June 24, 1971 211 App]. No.: 156,510

[52] US. Cl 260/240 R, 424/248, 424/267,

OTHER PUBLICATIONS Corey et al., J. Am. Chem. Soc., vol. 92, pages 2586to 2587, Apr. 22, 1970.

Primary ExaminerJohn D. Randolph Attorney, Agent, or Firm-Paul L.Sabatine, Edward L. Mandel]; Steven D. Goldby [57] ABSTRACT Novel 5 ',6'-dihydro-2l-l-pyran-4'-yl ether compounds of the formula prostaglandinwherein R is ma ma 'iewerair 'igm and R are hydrogen when Y is a singlebond and R R are absent when Y is a double; bond;

R is;

[451 Dec. 10, 1974 R is hydrogen or c when X is a double bond; and

when X is a single bond;

when X is a double bond and when X is a single bond; Z is a cis or transor CH CHz-; n is l to 5; m is 0 to 5i and the nontoxic salts. The novelcompounds possess pharmacological properties as modifiers of smoothmuscle activity, gastric secretion, blood pressure, lipolysis and thereproductive system. The compounds also induce labor and menses and theycan be used for the relief of asthma and nasal congestion and asplatelet anti-aggregation agents. a

21 Claims, No Drawings NOVEL 5', 6-DIHYDRO-2H-PYRAN-4'-YL PROSTAGLANDINETHERS DESCRIPTION OF NOVEL COMPOUNDS This invention relates to bothnovel and useful 5,6-dihydro-2l-I-pyran-4-yl prostaglandin ethers asrepresented by Formula Forn ula l a 1-2 in (CH CH3 R is a memberselected from the group consisting of hydrogen and C is a memberselected from the group consisting of when X is a double bond and H C 1swhen X is a single bond; C is a member selected from the groupconsisting of c n and when X is a double bond and C is a member selectedfrom the group 7 1 when X is a single bond; 2, is a member selected fromthe group consisting of cis and trans CI-I=CH and saturated CI-I CH Z isa member selected from the group consisting of trans CI-I=Cl-I- andsaturated .CH Cl-I X is a member selected from the group consisting ofsingle and double bonds with the proviso as set forth for C and C above;Y is a member selected from the group consisting of single and doublebonds with the proviso as set forth for R and R above; n is l to andm'is O to 5; and the non-toxic salts thereof.

The term lower alkyl appearing above and elsewhere in the presentspecification denotes a straight or branched chain alkyl group of 1 to 8carbon atoms inclusive, such as, methyl, ethyl, n-propyl, isopropyl,nbutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl,

'n-oxtyl, heptyl, and the like.

The pharmaceutically acceptable, non-toxic salts of the novel5',6'-dihydro-2l-I-pyran-4-yl prostaglandin ethers of Formula 1 (R =I-I)can also be used and they include the non-toxic alkali metal and thenon-toxic alkaline earth metal bases such as sodium, potassium, calcium,copper, and magnesium, the hydroxides and carbonates thereof, and theammonium salts and substituted ammonium salts, for example, thenon-toxic salts of trialkylamines such as trimethylamine, triethylamineand triisopropylamine, and other organic amines such as morpholine,diethylamine, dimethylamine,

DESCRIPTION OF INVENTIVE EMBODIMENTS The stereochemistry used for theprostaglandin compounds of the invention is the art acceptedstereochemistry. That is, the stereochemistry of the substituents bondedto the carbon of the S-membered cyclopentane ring may be oz-oriented orB-oriented as indicated by a wavy line. The dashed line indicates ana-orientation and the solid wedged line a B-orientation.Alphasubstituents are oriented on the opposite side of the cyclopentanering as the w-terrninal chain and ,B-substituents are oriented in theopposite sense, that is, on the same side as the alkyl side chain. Thesubstituents attached to the alkyl side chain may have a sinister (S) orrectus (R) configuration, which for the projection of these compoundsshown, is the equivalent nomenclature of a and ,8 respectively. The5,6-dihydro-2I-lpyran-4-yl prostaglandin ethers depicted by Formula 1and elsewhere in the specification and the accompanying claims includesthe analogues and all the cliastereomers thereof, and in addition in theenantiomeric forms .and such mixtures as are designated racemates. The

stereochemistry nomenclature and in addition the numbering systememployed herein is disclosed in Progress In The Chemistry of Fats AndOther Lipids, Vol IX; Part 2, pages 233 to 273, 1968, Pergamon Press,New York; and J. Lipids Research Vol 10, pages 316 to 319, 1969.

The novel 5,6'-dihydro-2H-pyran-4'-yl prostaglandin ethers of theinvention as represented by Formula 1 supra, and throughout thespecification and the accompanying claims, are prepared from thecorresponding prostaglandin compounds (natural or synthetic) orprostaglandin intermediate compounds by separately converting them tothe appropriate prostaglandin ether compound of the invention bychemical means. The corresponding starting prostaglandin can berepresented by Formula 2:

h r in .13 i rrs seni 31 n Rs e eb t i hxdmssn when Y is a single bondand R and R are absent when Y is a double bond; R is hydroxyl; R ishydrogen or hydroxyl;

Z is a cis or trans CH=CH- group or saturated --CH CH group; Z2 is atrans CH=CH- group or a CH CH group; x is a single bond when H C is Cand C is Z or H H H and X is a double bond when C and C are C ishydrogen or C is hydrogen,

wherein R is an NHCHO, NHCOCH NHCO-alkyl or Nl-l group, C Z & and m arepreviously defined, p is 4 to 7, and the enantiomeric forms.

The starting materials of Formula 2 used herein to synthesize thecompounds of Formula 1 are prepared in art known ways or they arereadily obtained from commercial sources. The starting materials offormula 2 are prepared by isolating the prostaglandin from naturalsources, for example, the vesicular glands of sheep, or by the enzymaticconversion from fatty acid substrates such as arachidonic acid, anddepending on the substituents desired, routinely chemically transformingdouble bonds to single bonds by hydrogenation, converting keto groups tohydroxymethylene groups by reduction, by dehydrating to introduce doublebonds. by forming carbinol derivatives by treating carbo(lower) alkoxygroups with an alkali metal alumino hydride reducing agent such aslithium aluminum hydride and the like. Specific prior art methods thatset forth the procedures useful for providing all of the natural andnaturally derived starting compounds embraced by Formula 2 are found inScience, Vol 158, pages 382 to 391, .1967; Recueil, Vol 85. pages 1233to 1256. 1966', Biochem. Biophys. Acid, Vol 106, pages 215 to 217. 1965;Agnew. Chem. Inter. Ed. Vol 4. pages 410 to 416. 1965; Experienlia, Vol21, pages 113 to 176, 1965; Recueil, Vol 85, pages i251 to 1253, 1966;and in other art recorded procedures.

The starting prostaglandin compounds and the starting materials depictedby Formulas 2 and 3 can also be chemically prepared by well-knownmethods. for example, from a common synthetic intermediate, 1 1,15-bis(tetrahydropyranyl)ether of 9a,! 1a,15(.S)- trihydroxy-5-cis,l3-trans-prostadienoic acid, to give the resulting prostaglandins asreported in J. Am. Chem. Soc, Vol 92, pages 2,586 to 2,587. 1970, andreferences therein; as prepared by the reduction of 2- oxa-3-oxo-6-exo-(trans-34S hydroxy-hept- 1 -enyl )-endo-7-acetoxy-cis-bicylo [3.3.0]octant followed by reduction and treatment with Wittig reagent to givethe corresponding prostaglandins as set forth in J. Am. Chem. Soc. Vol91. pages 5675 to 5677, 1969; by the total synthesis of prostaglandinsvia a tricarbocyclic intermediate as reported in Tetrahedron Letters,Vol 4. pages 307 to 310, 1970; by the total synthesis from2-oxabicyclol3.3.0]oct-6-en- 3-one, ibid, pages 3 10 to 31 l, 1970; andother reported chemcial synthesis embracing prostaglandins withinFormula 2 such as the J. Am. Chem. Soc.. Vol 90. pages 3245 to 3247,1968; ibid, Vol 91, pages 535 to 536, 1969; ibid, Vol 92, pages 397 to398, 1970; and in The Proceedings of the Robert A. Welch FoundationConference on Chemical Research, Vol X11, pages 51 to 79, 1969. Theprostaglandin starting materials embraced by Formula 3 are known to theart by the chemical synthetic route described in J. Am. Chem. Soc, Vol90, pages 3,245 to 3,247, 1968; and ibid, Vol 91 pages 535 to 536(1969).

The 5,6'-dihydro-2li-pyran reactants used to form the prostaglandinethers can be synthesized by wellknown procedures. For example,tetrahydroi-pyrone can be reacted with a lower alkanol under acidicconditions to form the intermediate4',4'-di(lower)alkoxytetrahydropyran, which upon dis tillation with anacid such as p-toluenesulfonic acid or mesitylenesulfonic acid yieldsthe 4'-lower alkoxy-S',6'-dihydro2H-pyran product. The lower al kanolsused include, for example, methanol, ethanol, n-propanol, isopropanol,n-butanol, isobutanol. pentanol, amyl alcohol, hexanol and the like, toform the cor responding pyran. The reaction of the 4'-loweralkoxy-S',6'-dihydro-2H-pyran with the starting materials of Formulae 2and 3 to give the desired 5,6'- dihydro-2l-l-pyran ether ofprostaglandin of the invention also produces small amounts of 4-lowera1koxy-tetrahydropyran- 4'-yl ethers of prostaglandin. To obtainincreased quantities of 5',6-dihydro-2H- pyran ether of prostaglandin,higher amounts of the acid catalysts and longer reaction times are usedto lead to increased yields of 5.6'-dihydro-2H-pyran-4-yl ethers ofprostaglandins. The formed products can also be separated byconventional chromatographic techniques using synthetic magnesiumsilicate, silica gel,

routine exchange resins, alumina and the like. The methods justdescribed are reported in J. Am. Chem. Soc., Vol 89, pages 3,366 to3,368, 1967, and in Tetrahedron, Vol 26, pages 1023 to 1030, 1970.

The 5,6'-dihydro-2H-pyran group is introduced onto the prostaglandinstarting materials of Formulae 2 and 3 by intimately contacting andreacting the prostaglandins free hydroxyl group under anhydrousconditions with an excess of 5',6'-dihydro-2H-pyran. Thehydroxy-prostaglandins are reacted, for example, with from about 1 toabout 25 or more molecular equivalents of the pyran under anhydrousconditions in the presence of an inert organic solvent and in thepresence of small amounts of acid catalysts. The reaction is usuallycarried out at a temperature of C to 75C, usually at room temperature,about 25C, for about 30 minutes to 96 hours, to produce from thestarting reactants and intermediates compounds that can be converted tothe corresponding compound of Formula 1.

Exemplary of suitable inert, organic solvents for performing thereaction generally include halogenated solvents such asmethylenechloride, chloroform, carbon tetrachloride and ethylenechloride, and other solvents such as tetrahydrofuran, dimethoxyethane,dimethylformamide, dimethylsulfoxide, dioxane, isobutyl ketone,cyclopentane, cyclooctane, n-hexane, n-heptane, mixtures thereof and thelike.

Representative of acid catalysts suitable for performing the reactionsare p-toluenesulfonic acid, hydrochloric acid, anhydrous hydrobromicacid, Lewis acids such as boron trifluoride, boron trichloride etherate,stannic oxychloride, phorphorous oxychloride, phosphorous pentachloride,zinc chloride, mixtures thereof, and the like.

The ,6'-dihydro-2H-pyran-4-yloxy prostaglandins (R =H) can be convertedto its non-toxic, pharmaceutically acceptable salt by neutralizing theprostaglandin with an equivalent or an excess amount of thecorresponding non-toxic salt forming organic or inorganic base. Thesalts are prepared by procedures known to the art, for example,equivalent or stoichiometric quantities of the prostaglandin and theorganic base are dissolved in an inert organic solvent at roomtemperature or in a warmed solvent with a gentle mixing of the reactingprostaglandin and the .base until all the reactants are in solution. Theproduct or salt is obtained by chilling the resulting mixture toprecipitate the powder or crystals, or the product can be isolated bythe addition of a miscible diluent of low polarity, or by the use ofstandard evaporation techniques. The formation of inorganicpyran-prostaglandin salts is also carried out by procedures known to theart; for example, the prostaglandin is dissolved in an aqueous solutioncontaining stoichiometric amounts or an excess amount of a nontoxic baseforrning inorganic sodium, calcium and potassium salts, or the like.This reaction can be carried out in the presence of an inert organicsolvent, and the product isobtained by procedures such as theevaporation of the aqueous medium, or the organic medium, by theaddition of miscible solvents of low polarity, or by chilling themixture to precipitate the product.

The lower alkyl esters of the compounds are obtained by art knownprocedures, such as, the treatment of the prostaglandin acid with asolution containing diazo(- lower)alkanes to produce the prostaglandinester. Es-

terification of the prostaglandin acid is performed by reacting the acidwith the diazoalkane, for example, diazomethane, diazoethane,diazopropane, diazobutane etc., in an inert organic solvent, forexample, lower alkanols, symmetrical and unsymmetrical ethers,halogenated solvents. Examples of solvents are ethanol, methanol,diethyl ether, methylethyl ether, tetrahydrofuran, chloroform, etc., orwith mixturs thereof. The esterification reaction is performed at atemperature of 0C to 25C, usually at room temperature and atmosphericpressure, with the ester recovered by evaporation of the solvent andlike chemical techniques. The esteriflcation reaction is described inOrganic Chemistry, by Fieser and Fieser, pages to 181, 1944.

The following preparations are set forth as representative methodsillustrative of the spirit of the present invention. These preparationsare not to be construed as limiting the scope of the invention as otherfunctionally equivalent means will be readily apparent to those skilledin the subject art.

EXAMPLE 1 Formula 4 in 0.5 ml of dry dimethyl sulfoxide is added afterabout 5 minutes. The mixture is stirred at ambient temperature for 1.0hr, and the dimethyl sulfoxide is removed under reduced pressure, about0.1 mm, and the residue is diluted with distilled water. The pH of theaqueous phase is adjusted to 9-10 with solid potassium carbonate. Then,the neutral components are extracted with ethyl acetatezether (1:1)and'then aqueous phase is acidified with oxalic acid to pH about 3.Extraction with 1:1 pentanezether is followed by washing the extractswith saturated brine and then drying over anhydrous magnesium sulfate,to yield the desired 11,15- bis-dihydro-pyran of PGF EXAMPLE 2 Synthesisof l 1 l 5-bis( 5 ',6 '-d'ihydro-2H-pyran-4'- yloxy )-9-oxo-5-cis, 13trans-prostadienoic acid,

(1l, l5-bis-dihydropyran of PGE A mixture of the etone is cooled to l C.Then, 59.0 ll of Jones Reagent is added over minutes with constantstirring. After an additional 25 minutes at l0C, 59 pl of isopropylalcohol is added and after 5 minutes the mixture is diluted with ml ofethyl acetate. The organic phase is separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate to yield 1 l, l5-bis-dihydro-pyran of PGE EXAMPLE 3 Synthesis of l l l 5-bis( 5',6'-dihydro-2l-l-pyran-4- yloxy-l 3-trans-prostenoic acid, l l lS-bis-dihydropyran OQPGFM). A rnixture of 0.08 mmol of 11,15 hi$r hy -P.n f PGFZM sL 2 la99u ins1 Example 1, and 9.6 mg of 5% Pd/C in 5.0 ml ofdry methanol is hydrogenated at l 5C to 20C at atmospheric pressure.After 3 hrs. the mixture is filtered through Celite 545 and concentratedin vacuo to give the product, also containing small amounts of 13,14-dihydro-bis-(dihydro-pyran) of PGFm.

EXAMPLE 4 Synthesis of l l l 5-bis(5 ',6'-dihydro-2l-l-pyran-4-yloxy)-9-oxo-l 3-trans-prostenoic acid, 1 l ,l5-bisdihydro-pyran of PGETo a solution, cooled to about -l0C of the compound prepared in Example3 in 1.5 ml of acetone is added 59.5 pl of Jones Reagent. After stirringfor 5 minutes at l0C, 59.5 pl of isopropyl alcohol is added and stirringis continued for 5 minutes at 10C. Then, after dilution with ethylacetate, the organic phase is washed with distilled water and saturatedbrine, dried over anhydrous magnesium sulfate and concentrated to yieldthe product.

EXAMPLE 5 To a mixture of 0.5 g of 901,] la, 1 5(S)-trihydroxyl 3-transprostenoic acid and 10 cc of dry benzene there is added 2 cc of4'-methoxy-5',6'-dihydro-2H-pyran and about 5 ml of the mixture anddihydropyran is distilled off to remove moisture, then, the remainingmixture is cooled to room temperature. To the cooled mixture is thenadded 0.03 g of p-toluenesulfonic acid and the resulting mixture isallowed to stand at room temperature for about 50 hours. Following thisreaction period, the reaction mixture is diluted with 10 ml of ethylacetate, washed with an aqueous 5 percent sodium carbonate solution andthen with distilled water until an essentially neutral pH is obtainedfor the mixture. Finally, the neutral organic phase is dried overanhydrous sodium sulfate and evaporated to dryness. The dry residue isthen chromatographed by passing it, dissolved in hexane, (containing alittle ethyl acetate) through a column of neutral silica to yield 901,1lae,l5(S)- tris(5,6'dihydro-2H-pyran-4 -yloxy)- l 3-trans- BF9EQ9LQE1SLEXAMPLE 6 Repeating the procedure of Example 5 but replacing 9a,l 1oz,(S )-trihydroxyl 3-trans-prostenoic acid with:

9B, 1 la, 1 5(S)-trihydroxyl 3-trans-prostenoic acid,

90:, l 102,] 5(S)-trihydroxy-5-cis, l 3-transprostadienoic acid,

98,1 101,1 5 S )-trihydroxy-5-cis, l 3-transprostadienoic acid,

913,1 lB,l 5( R)-trihydroxyl 3-trans-prostenoic acid,

racemic 9B,] 113,15(R)-trihydroxy-5-cis,l 3-transprostadienoic acid,and, 7

tris(5 ',6-dihydro-2H-pyran-4-yloxy)- l 3-transprostenoicacid,

racemic 901,1 la, 1 5( R)-tris(5 ,6'-dihydro-2H-pyran- 4'-yloxy)-5-cis,l3-trans-prostadienoic acid,

9a,1 la,l 5(S)-tris(5',6'-dihydro-2H-pyran-4 -yloxy 5-cis, l3-trans-prostadienoic acid, and,

901,1 la, 1 5(S )-tris(5 ',6'-dihydro-2H'pyran-4'-yloxy 5-cis,1 3-trans,l 7-cis-prostatrienoic acid.

EXAMPLE 7 To a solution of 500 mg ofl5(S)-hydroxy-9-oxol0,l3-transprostadienoic acid and 20 ml of methylenechloride at 25C there is added an excess, l5 ml of freshly prepared4'-methoxy-5',6'-dihydro-2H-pyran and 40 mg of anhydrousp-toluenesulfonic acid catalyst, and the mixture is gently stirred forabout 15 to 20 minutes. Next, the reaction mixture is quenched by addingabout 5 to 6 drops of pyridine and it is diluted with about 50 ml ofether. Then, the mixture is washed with 10 m1 aliquots of 50% brine andwith 10 ml of saturated brine. Finally, the extracted organic phase isdried over anhydrous magnesium sulfate and concentrated under housevacuum to dryness. The dry residue is then chromatographed by passingit, dissolved in hexane containing a little ethyl acetate, through acolumn of neutral alumina, to give l5(S)-(5',6'-dihydro-2H-pyran-4-yloxy)-9-oxol0, 3-trans-prostadienoic acid.

EXAMPLE 8 Repeating the procedure of Example 7 but substituting forl5(S)-hydroxy-9-oxo- 10, l 3-trans-prostadienoic acid the following:

l5( S)-hydroxy-9-oxo-5-cis,l 0, l 3-transprostadienoic acid,

l 5( R )-hydroxy-9-oxol 0, l 3-trans-prostadicnoic acid,

l5(Rl-hydroxy-9-oxo-5-cis.10,13-trans-prostatrienqisa ila o 15(8), 19-dihydroxy-9-oxol 0,1 3-transprostadienoic, the following novel ethersare formed:

l 5(S )-(5 ,6-dihydro-2H-pyran-4 yloxy )-9-oxo5- cis, l 0, l3-trans-prostatrienoic acid,

l5(R)-( 5 ,6 '-dihydro-2H-pyran-4yloxy )-9-oxo- 10,13-transprostadienoic acid,

l5( R)-( 5 ,6'-dihydro-2H-pyran-4yloxy )-9-oxo-5- cis,10,l3-trans-prostatrienoic acid, and,

l5(S l 9-bis( 5 ,6'-dihydro-2H-pyran-4yloxy )-9- oxol 0, l3-trans-prostadienoic acid.

EXAMPLE 8 To a 500 ml roundbottom borosilicate flask containing 0.4 g ofmethyl-15(S)-hydroxy-9-oxo-8( l2),l3- trans-prostadienoate in 15 ml ofbenzene there is added 2 ml of fresh 4-ethoxy-5',6'-dihydro-2H-pyran and0.06 ml of phosphorous oxychloride and the flask heated to about 30C forl V2 hr. Next, the solution is cooled to room temperature and dilutedwith 50 ml of ether, washed with 50% brine and saturated brine until thesolution is neutral. Next, the organic phase is dried over anhydrousMgSO filtered and freed of solvent EXAMPLE 9 Following the procedure ofExample 8, but replacing hy 1 5(S )-hydroxy-9-oxo-8( l 2),13-trans-prostadienoic acid with:

EXAMPLE 1O To 450 mg of9-formylamino,l1a,15(S)-dihydroxyl3-trans-prostenonitrile, having thefollowing structure, Formula 5 NHCHO Formula 55 are prepared accordingto J. Am. Chem. $00., Vol 90, pages 3245 to 3248, 1968, in 10 ml ofmethylene chloride there is added 1.5 ml of distilled 4'-methoxy-5',6'-dihydro-2l-Lpyran and 5 mg of anhydrous p-toluenesulfonic acid and themixture stirred for about minutes at room temperature. After quenchingthe reaction with a few drops of pyridine and ether, the product isobtained by evaporation of the solvent in vacuo. Next, the product9-formamido, 1 101,15(S)-bis(5',6'-dihydro- 21-l-pyran-4-yloxy)- l3-trans-prostenonitri1e, of the following structure, Formula 6:

Fornullu 6 EXAMPLE 1 1 Following the procedure of Example 12, butreplacing 9-formamido-l l a, 1 5(S )-dihydroxyl 3-transprostenonitrilewith:

racemic 9-formamido-1 1,B,15(S)-dihydroxyl 3- trans-prostenonitrile,

racemic 9-formamido- 1 101,1 5(R)-dihydroxy- 1 3 trans-prostenonitrile,

racemic 9-formamido-1 1,8,15(R)-dihydroxyl 3- trans-prostenonitrile,and,

enantio 9-formamidol 1 B, l 5(R)-dihydroxy- 1 3- trans-prostenonitrile,also prepared by the method outlined in J. Am. Chem. Soc, Vol 90, pages3245 to 3248, 1968; the following ethers are formed: v

racemic 1 1,8,1 5(S)-bis (5 ',6'-dihydro-21-l-pyran-4'- y1oxy)-9-oxo- 13,-trans-prostenoic acid,

racemic 1 104,15(R)-bis(5',6-dihydro-21-1-pyran-4- yloxy)-9-oxo- 13-trans-prostenoic acid,

racemic l 1 13,1 5(R)-bis(5 ,6'-dihydro-2l-l-pyran-4'- yloxy)-9-oxo- 13-trans-prostenoic acid, and,

enantio l 13,15(R)-bis(5',6'-dihydro-2l-l-pyran-4- yloxy)-9-oxo- 13-trans-prostenoic acid.

EXAMPLE 12 The compounds, 9B-hydroxy, 1 1a,15(S)-bis(5',6'-dihydro-2l-l-pyran-4-yloxy)- 1 3trans-prostenoic and 9 ,B-hydroxy, 1104,15(S)-bis(5',6'-dihydro-2H-pyran-4'- yloxy)- 1 3-trans-prostenoicacid are prepared by the reduction of the corresponding 11a,l5(S)-bis(5,6- dihydro-21-1-pyran-4'-yloxy )-9-oxo- 13-trans-prostenoic acid using NaB(R),,l-l., wherein R is a lower alkylof l to 4 and n is 0 to 4, in an inert organic solvent at 0C to 30C for15 minutes to 1 hour to give the set forth prostaglandin ethercompounds. For example, the reduction is performed with sodiumborohydride in methanol at 0C for 30 minutes followed by chromatographicseparation to give the prostaglandin ethers.

EXAMPLES 13 to 16 The oz-homo analogues of ll,l-bis(5',6'-dihydro-2I-I-pyran-4'-yloxy)-5-eis, l 3-trans-prostadienoic acid,

(11,15-bis-dihydro-pyran of PGFM); of 11,

EXAMPLE 17 In this preparation, the l5-epimer of the hemi-acetalemployed in Examples 13 to 16 inclusive, also prepared by the method asset forth in J. Am. Chem. 500., Vol. 92, pages 2,586 to 2,587, 1970, andthe references cited therein, and shown here as Formula 7 as follows:

Formu 1 ii 7 in either this form, or as the enantiomer is reacted with16 to produce the following prostaglandin ethers:

1 la, 1 5( R )-bis( 5 ',6'-dihydro-2I-I-pyran-4 '-yloxy9a-hydroxy-5-cis, l3-trans-prostadienoic acid,

enantio l 1a,15(R)-bis(5',6'-dihydro-2l-I-pyran-4-yloxy)-9a-hydroxy-5-cis, l 3-trans-prostadienoic acid,

1 loz,15(R)-bis(5 ',6-dihydro-2H-pyran-4 -yloxy)-9- oxo-S-cis,l3-trans-prostadienoic acid, and,

enantio 1 la, 1 5(R)-bis(5 ',6'-dihydro-2H-pyran-4- yloxy)-9-oxo-5-cis,l 3-trans-prostadienoic acid.

EXAIVIPLE l 8 l1a,]5(S)-bis(5,6'-dihydro-2I-I-pyran-4'-yloxy)-9- oxo- 13-trans-8iso-prostenoic acid,

1 1 04,1 5(S)-bis(5 ,6-dihydro-2l-I-pyran-4'-yloxy)-9- oxol3-trans-co-homo-prostenoic acid,

9a,l la,l5(S)-tris(5',6'-dihydro-2I-l-pyran-4'-yloxy)- 5-cis,l3-trans-prostadienoic,

butyl 904,1 1a,] 5( R)-tris(5 ',6'-dihydro-2H-pyran-4'- yloxy)-S-cis, l3-trans-prostadienoate,

901,1 10s,15(S)-tris(5,6-dihydro-2I-I-pyran-4yloxy)- 5-cis, l3-trans, l7-cis-prostatrienoic acid,

ethyll 5( S )-5 ,6'-dihydro-2I-l-pyran-4'-yloxy-9-oxol0, 13-trans-prostadienoate,

15(S )-5 ',6-dihydro-2H-pyran-4'-yloxy-9-oxo-5 cis,10, l3-trans-prostatrienoic acid, and,

methyl- 1 5( S)- 191 -bis(5 ',6-dihydro-2H-pyran-4 yloxy )-9-oxol O, l 3,trans-prostadienoate.

DESCRIPTION OF INVENTIVE APPLICATIONS The novel prostaglandin ethers ofthe invention as embraced by Formula I possess valuable and usefulproperties. The prostaglandin ethers are inventively characterized bytheir ability to serve as a source of the parent prostaglandin followingthe controlled meta bolic hydrolysis of the prostaglandin from 5'.6-dihydr0-2H-pyran-4yl moiety. For example. prostaglandin ethers with aC keto group and one or both of the (I and R positions substitured witha 5,6-dihydro-2H- pyran-4'-yl group on, for example, in vivo separationof the latter group with formation of hydroxyl groups make availableprtxstaglandins that possess valuable pharmacological properties,including the ability to lower blood pressure and relieve asthma LIIILInasal eongcstion. These formed parent prostuglandins are useful for themanagement of hypertension in avians, mammals, including humans, farmanimals and for scientific studies using laboratory animalsv Also,following the separation of the 5',6-dihydro2H-pyran-4-yl groups andwith concomitant formation of hydroxyl groups in vivo, these willproduce for example, 1 104,156)- dihydroxy-9-oxo5-cis, l3-trans-prostadienoic acid, the latter compound when administered at therate of 0.5 ug/min/kg intravenously, or 2 mgr 2 hrs intravaginally, or0.5 rug/2 hrs orally, is known to be effective in humans for theinduction of labor. Representative prostaglandin ethers for obtainingprostaglandins that possess the set forth pharmacological propertiesinclude 1 la, 1 5(S)-bis(5 ,6-dihydro-2H pyran-4'-yloxy)-9-oxol 3-trans-prostenoic acid; I la, 1 5(S)-bis(5',6'-dihydro-2I-lpyran-4-yloxy)-9-oxo-5-cis, l 34rans-prostadienoic acid; 1 la, 1 5(S) bis( 56'-dihydro-2H-pyran-4'- yloxy)-9-oxo-5-cis,l 3trans, l7-cis-prostratrienoic acid and the like.

The prostaglandin ethers of the invention as represented by Formula 1and substituted at the C C3. and R positions with a5',6'-dihydro-2H-pyran-4'-yl group on separation of the latter groups,and with concomitant in vivo formation of hydroxyl groups at the C C andR, positions, will produce prostaglandins possessing smooth musclestimulating activity, for example.

904,1 104,15(S)-trihydroxy-l3-trans-prostenoic acid, 90:,

1 101,1 5(S)-trihydroxy-5-cis, l 3-trans-prostadienoic acid, and thelike, which latter compounds when ad ministered intravenously (5g/kg/min.) or intravaginally (25 mg/2 hrs.) will induce labor inmammals, including humans. Exemplary of novel prostaglandin ethers thatfurnish the corresponding prostaglandins which latter prostaglandinspossess smooth muscle ac tivity are 9a,] 1041 (S )-tris( 5,6'-dihydro-2l-l-pyran-4- yloxy)-l 3-trans-prostenoic acid; 901,1 lot, 15(S tris(5',6-dihydro-2l-l-pyran-4-yloxy)-5-cis,13-transprostadienoicacid; 9a,l la, 1 5(S )-tris( 5 ,6-dihydro- 2l-l-pyran-4-yloxy )-5-cis,13-trans, l 7-cisprostatrienoic acid, and the like.

The prostaglandin ethers of the invention that supply in vivo aphysiologically active prostaglandin characterized by a C, keto groupand l) a C and R, hydroxyl group according to Formula 1 or (2) a C C andR,

hydroxyl group according to Formula 1 are physiologically useful for notonly inducing labor but also menses and for the termination ofpregnancy. Representative of prostaglandin ethers that can serve as anin vivo source of physiologically active prostaglandins whenadministered for example, intravenously, at the rate of 0.1 to 1.0ag/min, calculated as freed prostaglandins are ethers such as 9a,]lal5(S)-tris(5',6'-dihydro-2H- pyran-4'-yloxy )-l 3-trans-prostenoicacid; 9011 la, 1 5(S- )-tris( 5 ',6'-dihydro-2l-l-pyran-4-yloxy)-5-cis,l 3-transprostadienoic acid; 901,1 la,l5(S)-tris(5', 6-dihydro-2H-pyran-4'-yloxy)-5-cis, l 3-trans,17-cisprostatrienoic acid; 1la,l5(S)-bis-9-oxo-5-cis,l3- trans-prostadienoic acid; 1 la, 1 5(S)-bis( 5 ,6-dihydro- 2H-pyran-4'-yloxy)-9-oxol 3-trans-prostenoic acid;and the like.

The novel prostaglandin ethers can be used for the relief of asthma,nasal congestion and inhibition of lipolysis by supplying fromprostaglandin ethers of Formula l and substituted with a C, keto and aR, 5',6'- dihydro-ZH-pyran groups or a prostaglandin ether substitutedwith a C, keto and at C and R, with a 5',6'- dihydro-2H-pyran group thecorresponding parent prostaglandins' possessing the desired therapeuticutility. Exemplary of prostaglandin ethers of the invention forproducing the corresponding prostaglandins include l5(S)-(5',6-dihydro-2H pyran-4'-yloxy)-9- oxol 0, l 3-trans-prostadienoic acid;l5(S)-(5 ,6'- dihydro-2H-pyran-4'-yloxy )-5-cis, l0, 1E-transprostatrienoic acid; 1 la, 1 5(S)-bis(5',6'-dihydro-2H-pyran-4'-yloxy )-9-oxo-5-cis, l 3-trans-prostadienoic acid; and thelike,

The prostaglandin ethers of Formula 1 of the invention substituted witha C, keto group and additionally with a R, or a C and R,5',6"dihydro-2H-pyran-4- yloxy group are useful for the management ofgastric secretions. These prostaglandin ethers release the naturalanti-secretory prostaglandin in the stomach upon the acidic hydrolysisof the prostaglandin ether to free the prostaglandin group of theprostaglandin ether from the affixed pyranyloxy moiety. Theprostaglandin ethers ability to release free prostaglandin undergastric-like environmental conditions is demonstrated by standard invitro experiments using an artificial gastric juice consistingessentially of mineral acid, hydrochloric, at varying pH from 1 to 4.5at 37C. For example, 1 la, 1 5(S)-bis( 5',6-dihydro-2H-pyran-4-yloxy)-9- oxo-5-cis,l3-trans prostadienoic acidreleases active 1 1a,] 5(S)-dihydroxy-9-oxo-5-cis, l3-transprostadienoic acid at pH 2 to 4 and at 37C. The immediatelydescribed prostaglandin ethers are therapeutically indicated forregulating gastric secretions, that is, hypcracidity, because as the pHof the stomach reaches 4.5 to 5 the hydrolysis of the prostaglandinether is essentially decreased, and, as the prostaglandin ether passesfrom the stomach into the intestine, the unwanted increased intestineperistalsis or increased intestinal motility with the accompanying bowelactions and diarrhea following administration of the natural form of theprostaglandins in the intestine are essentially absent for theprostaglandin ethers of the invention.

The prostaglandin ethers ability to release prostaglandin is determinedby standard laboratory techniques, for example, by adding small amounts,10 micrograms, 50 micrograms, etc., of the prostaglandin ether tohydrogen'ion environments at varying pH and then detecting the presenceof freed prostaglandin by conventional muscle bioassay. For example, theaddition of 911,1 la, 1 5(S)-tris(5,6-dihydro-2H-pyran-4-yloxy)-5-cis,l3-trans-prostadienoic acid, and for racemic 905,] la 15(S)-tris-(5 ',6-dihydro-2l-l-pyran-'4yloxy)-5-cis,l3-trans-prostadienoic acid to a hydrogen ion environment,hydrochloric acid, indicated by bioassay, for example contraction ofisolated rat uterine or gerbil colon strips, that from about pH 1 to4.5, controlled hydrolysis of the ether linkage occurs to releasedeterminable quantities of the corresponding prostaglandin.

Theprostaglandin ethers of the invention possess desirable partitioncoefiicients that are seemingly not present in prior art prostaglandinsbetween aqueous and lipid phases and they are therefore adaptable foradministering for their physiological effects from drug deliverysystems, such as intrauterine contraception devices, skin drug deliverybandages and the like, manufactured from naturally occurring andsynthetic polymeric materials. This novel and useful property of theprostaglandin ethers make possible their diffusion at measurablecontrolled rates through polymeric materi als such as polyvinylchloride,polyisoprene, polybutadiene, polyethylene, ethylene-vinyl acetate,collagen, polydimethylsiloxanes, hydrophilic hydrogels of esters ofacrylic and methacrylic acids, polyvinyl acetates, propylene vinylacetate copolymers, and the like.

The novel prostaglandin ethers of the invention can I be used by thepharmaceutical and the veterinary arts in a variety of pharmaceuticalpreparations or veterinary preparations. ln these preparations, the newcompounds are administrable in the form of tablets, pills, powders,capsules, injectables, solutions, suppositories, emulsions, dispersions,food premix and in other suitable forms. The pharmaceutical orveterinary preparation which contains the compound is convenientlyadmixed with a non toxic pharmaceutical organic carrier or a non-toxicpharmaceutical inorganic carrier. Typi cal of pharmaceuticallyacceptable carriers, are for example, water, gelatine, lactose,starches, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, petroleum jelly and ther conventionally employedpharmaceutically acceptable carriers. The pharmaceutical preparation mayalso contain non-toxic auxiliary substances such as emulsifying,preserving, wetting agents and the like, as for example, sorbitanmonolaurate, triethanolarnine oleate, polyoxyethylene sorbitanmonopalmityl, dioctyl sodium sulfosuccinate, and the like.

Exemplary of a typical method for preparing a tablet 7 containing theactive ingredient is to first suitably comminute the active ingredientwith a diluent such as starch, sucrose, kaolin or the like to form apowder mixture. Next, the just prepared mixture can be granulated bywetting with a non-toxic binder such as a solution of gelatin, acaciamucilage, corn syrup and the like and after mixing the composition isscreened to any predetermined particle sieve size. As an alternative, ifpreferred to granulation, the just prepared mixture can be sluggedthrough conventional tablet machines and the slugs comminuted before thefabrication of the tablets. The freshly prepared tablets can be coatedor they EXAMPLE 1) Per tablet m 1 Prostaglanclin ether 2.0 Com starchl5.0 Com starch paste 4.5 Lactose 82.0 Calcium steamte 2.0 Dicalciumphosphate 50.0

To formulate the tablet, unifonnly blend the prostaglandin ether, cornstarch, lactose and dicalcium phosphate in a V-blender until all theingredients are uniformly mixed together. Next, the corn starch isprepared as a l percent aqueous paste and it is blended with the uniformmixture until a uniform mixture is obtained. Then, the wet granulationis passed through a standard eight mesh screen, dried and rescreenedwith a twelve mesh screen. The dry granules are next blended withcalcium stearate and compressed into tablets. other tablets containing0.05, 0.25, 1.0, 5.0, l0.0 mgs. etc. are prepared in a like fashion.

The manufacture of capsules containing 0.1 milligram to 500 milligramsfor oral use consists essentially of mixing the active compound with anon-toxic carrier and enclosing the mixture in a gelatin sheath. Thecapsules can be in the art known soft form of a capsule made byenclosing the compound in intimate dispersion within an edible-oil orthe capsule can be a hard capsule consisting essentially of the novelcompound mixed with a non-toxic solid such as talc, calcium stearate,calcium carbonate or the like. Exemplary of a typical use employingcapsules containing 25 mg, of 11a,-l(S)-bis(5',6'-dihydro-2H-pyran-4'-yloxy)-9-oxo-1 3- trans-prostenoicacid is therapeutically indicated per diem for inhibiting gastricsecretions with lesser amounts indicated as the pH of the stomach ofabout 4 to 5.

The daily dose administered for the compounds will of course vary withthe particular novel prostaglandin ether employed because of the varyingpotency of the compounds, the chosen route of administration and thesize of the recipient. The dosage administered is not subject todefinite bounds, but it will usually be an effective amount or theequivalent on a molar basis, of the pharmacologically active free acidfonn produced upon the metabolic release of the prostaglandin to achievethe biological function of the prostaglandin. Represnetative of atypical method for administering the 5,6'-dihydro-2H-pyran-4'-yloxyprostaglandin ethers of the invention is by the injectable-typeadministration route. By this route, a sterile solution containing thecompound is administered intravenously or subcutaneously at the rate of0.01 microgram to 0.50 microgram per kilogram of body weight per minuteby means of an infusion pump at the rate of 10 to l 5 milliters perhour. For example, the compound 901,1 la, 15(- S)-tris-(5,6'-dihydro-2H-pyran-4'-yloxy l 3-transprostenoic acid can beadministered by this route for producing stimulation of smooth muscles;1 lrx,l5(S)- bis( 5 ',6'-dihydro-2H-pyran-4 '-yloxy l-9-oxol3-transprostenoic acid can be administered by this route for regulatingthe acidic gastric concentration and the volume of gastric secretion.Another typical method for administering the prostaglandin ether is bythe oral route. By the oral route, 10 ug to pg per kg of recipient perday is administered to evoke the desired effects. Thus, for a typical 75kg recipient the daily dose is about 750 ug to 4125 pg. The compound isadministered by the injectable route in a fonn suited for injection,such as mixed with sterile physiological saline, or in aqueous solutionshaving incorporated therein an agent that delays absorption such asaluminum monostearate and the like.

Suitable topical preparations containing the novel prostaglandin etherscan easily be prepared by, for example, mixing 500 mg. of the5,6-dihydro-2H-pyran- 4'-yloxy prostaglandin with l5 g of cetyl alcohol,1 g of sodium lauryl sulfate, 40 g of liquid silicone DC. 200 sold byDow Corning Co., Midland, Michigan, 43 g of sterile water, 0.25 g ofmethylparaben and 0.l5 g of propylparaben and warming the mixture withconstant stirring to about 75C and then permitting the preparation tocongeal. The preparation containing the prostaglandin ether can bereadily applied to the skin by inunction or it can be applied topicallyby dispensing the preparation from a conventional surgical gauzedispenser, and the like. The prostaglandin ethers penetrate theoutermost layer of the skin, the stratum corneum, more readily thanunetherified prostaglandins and as such the prostaglandins' ethers lendthemselves to topical administration. Suitable procedures for preparingtopical applications are set forth in Remingions PharmaceuticalScience,Chapter 37, as cited supra.

The compounds of this invention can also be conveniently administered inaerosol dosage form. An aerosol form can be described as aself-contained sprayable product in which the propellant force issupplied by a liquified gas. For administering a self-propelled dosageform of about l mg to 500 mg that is used about 3 or 4 times daily forinhalation therapy, the bronchodialator l la,l5(S)-bis(5',6'-dihydro-2H-pyran-4-yloxy )-9- oxo-5-cis,l3-trans prostadienoic acidis suspended in an inert non-toxic propellant in a commerciallyavailable compressed-gas aerosol container. Suitable propellants includetrichloromonofluoromethane, dichlorodifluoromethane,dichlorodifluoroethane, monochlorodifluoroethane and mixtures thereof.The inert gas can also be mixed with non-toxic cosolvents such asethanol, if desired, to produce the aerosol form. If the compound isadministered by oral inhalation employing conventional nebulizers, it isconvenient to dilute in an aqueous solution about 1 part of the novelprostaglandin with about l000 to 10,000 parts of solution, foradministering three or four times per day,

For administering to valuable domestic household, sport or farm animalssuch as sheep, goats, cattle. etc,

or for administering to laboratory animals for scientific studies, thecompound is prepared in the form of a food premix, such as mixing withdried fish meal, oatmeal, straw, hay, ground corn, mash, and the like,and then the prepared premix is added to the regular feed,

thereby administering the compound to the domestic or laboratory animalin the form of feed.

ln laboratory studies for determining the applicability of theprostaglandin ethers to mammals, including humans, avians, and valuableanimals, the studies are carried outwith rats, mice, etc. For example,in laboratory gastric anti-secretory studies with standard whitelaboratory rats, the compound 9a, lloz,l5(S)-tris(5'6dihydro-2H-pyran-4-yloxy)- l 3-trans-prostenoic acid is administeredorally by perfusion in saline at' the rate of 0.1 microgram to 1.0microgram per minute across the mucosal surface of the stomach toessentially inhibit release of titratable acidity.

The above examples and disclosure are set forth merely for illustratingthe mode and the manner of the invention and various modifications andembodiments can be made by those skilled in the art in the light of theinvention without departing from the spirit of the invention.

We claim:

1. Novel compounds of the formula:

R is a member selected from the group consisting of hydrogen and C is amember selected from the group consisting of C is a member selected fromthe group consisting of Q, is a member selected from the groupconsisting of and Z, is a member selected from the group consisting ofcis and trans -CH=Cl-l and -CH Cl-l Z is a member selected from thegroup consisting of trans -Cl-l=Cl-l and CH2CH X is selected from thegroup consisting of a single bond and double bond and X is a double bondwhen C and C are substituted with hydrogen; and wherein n is l to 5 andm is O to 5; the diastereomers and non-toxic salts thereof.

2. A'compound according to claim 1 wherein the compound is 11a,l5(S)-bis(5,6-dihyd ro-2H-pyran- 4'-yloxy)-9-oxo-l 3-trans-prostenoicacid.

3. A compound according to claim 1 wherein the compound is 1 la, 15(S)-bis( 5 ',6-dihydro-2H-pyran- 4'-yloxy)-9-oxo-5-cis,l3-trans-prostadienoic acid.

4. A compound according to claim 1 wherein the compound is l101,15(S)-bis(5',6-dihydro-2H-pyran- 4-yloxy )-9-oxo-5-cis, l 3-trans, l7-cis-prostatrienoic acid.

5. A compound according to claim 1 wherein the compound is1101,15(S)-bis(5',6'-dihydro-2l-l-pyran- 4'-yloxy)-9-oxol3-trans-w-homo-prostenoic acid.

6. A compound according to claim 1 wherein the compound is lla,l5(S)-bis(5',6'-dihydro-2H-pyran- 4'-yloxy)-9-oxol 3-trans-8-iso-prostenoic acid.

7. A compound according to claim 1 wherein the compound is l101,15(S)-bis(5',6'-dihydro-2H-pyran- 4'-yloxy)-9-oxo-prostanoic acid.

8. A compound according to claim 1 wherein the compound is 904,1 la, 15(S)-tris( 5 ,6"-dihydro-2H- pyran-4'-yloxy)-5-cis,l3-trans-prostadienoic acid.

9. A compound according to claim 1 wherein the compound is 904,1lal5(S)-tris(5 ',6-dihydro-2H- pyran-4 '-yloxy)-5-cis, l 3-trans, l7-cis-prostatrienoic acid.

10. A compound according to claim 1 wherein the compound isl5(S)-(5',6'-dihydro-2l-l-pyran-4'- yloxy)-9-oxol 0, l3-trans-prostadienoic acid.

11. A compound according to claim 1 wherein the compound is 15(S)-(5',6'-dihydro2H-pyran-4- yloxy)-9-oxo-5-cis, 10,1 3-trans-prostatrienoicacid.

12. A compound according to claim 1 wherein the compound is 15(8), 19-bis( S ,6'-dihydro-2l-l-pyran-4'- yloxy)-9-oxol O, l3-trans-prostadienoic acid.

13. A compound according to claim 1 wherein the compound is enantiol5(S)-(5,6'-dihydro-2l-l-pyran- 4-y1oxy)-9-oxolO,l S-trans-prostadienoicacid.

14. A compound according to claim 1 wherein the compound is 9a,l la, 15(S)-tris(5 ,6'-dihydro-2H- pyran-4-yloxy)-l 3-transprostenoic acid.

15. A compound according to claim l wherein the compound is 1 111,15(R)-bis(5 ',6'-dihydro-2Hpyran- 4'-yloxy)-9-oxol 3-trans-prosten oicacid.

16. A compound according to claim 1 wherein the compound is enantio lla,1 (R)-bis( 5 ',6-dihydro-2H- pyran-4'-yloxy)-9-oxolB-frans-prostenoic acid.

17. A compound according to claim 1 wherein the compound is lower alkyl1 la, 1 5(S )-bis( 5 ',6-dihydro- 2H-pyran-4'-yloxy)-9-oxol3-trans-prostenoate.

18. A compound according to claim 1 wherein the compound is 1 la, 15(S)-bis(5 ',6'-dihydro-2H-pyran- 4-yloxy)-9a-hydroxyl3-trans-prostenoic acid.

19. A compound according to claim 1 wherein the

1. NOVEL COMPOUNDS OF THE FORMULA
 2. A compound according to claim 1wherein the compound is 11 Alpha,15(S)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-13-trans-prostenoicacid.
 3. A compound according to claim 1 wherein the compound is 11Alpha ,15(S)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-5-cis,13-trans-prostadienoic acid.
 4. A compound according to claim 1 whereinthe compound is 11 Alpha,15(S)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-5-cis,13-trans,17-cis-prostatrienoic acid.
 5. A compound according to claim 1wherein the compound is 11 Alpha,15(S)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-13-trans-omega-homo-prostenoic acid.
 6. A compound according to claim 1 wherein thecompound is 11 Alpha ,15(S)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-13-trans-8-iso-prostenoicacid.
 7. A compound according to claim 1 wherein the compound is 11Alpha ,15(S)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-prostanoicacid.
 8. A compound according to claim 1 wherein the compound is 9 Alpha,11 Alpha ,15(S)-tris(5'',6''-dihydro-2H-pyran-4''-yloxy)-5-cis,13-trans-prostadienoic acid.
 9. A compound according to claim 1 whereinthe compound is 9 Alpha ,11 Alpha15(S)-tris(5'',6''-dihydro-2H-pyran-4''-yloxy)-5-cis,13-trans,17-cis-prostatrienoic acid.
 10. A compound according to claim 1wherein the compound is15(S)-(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-10,13-trans-prostadienoicacid.
 11. A compound according to claim 1 wherein the compound is15(S)-(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-5-cis,10,13-trans-prostatrienoic acid.
 12. A compound according to claim 1 wherein thecompound is15(S),19-bis(5'',6''-dihydro-2H-pyRan-4''-yloxy)-9-oxo-10,13-trans-prostadienoic acid.
 13. A compound according to claim 1 wherein thecompound is enantio15(S)-(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-10,13-trans-prostadienoicacid.
 14. A compound according to claim 1 wherein the compound is 9Alpha ,11 Alpha,15(S)-tris(5'',6''-dihydro-2H-pyran-4''-yloxy)-13-trans-prostenoicacid.
 15. A compound according to claim 1 wherein the compound is 11Alpha,15(R)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-13-trans-prostenoicacid.
 16. A compound according to claim 1 wherein the compound isenantio 11 Alpha,15(R)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-13-trans-prostenoicacid.
 17. A compound according to claim 1 wherein the compound is loweralkyl 11 Alpha,15(S)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9-oxo-13-trans-prostenoate.18. A compound according to claim 1 wherein the compound is 11 Alpha,15(S)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9 Alpha-hydroxy-13-trans-prostenoic acid.
 19. A compound according to claim 1wherein the compound is 11 Alpha,15(S)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)- Alpha-hydroxy-13-trans-prostenoic acid.
 20. A compound according to claim 1wherein the compound is racemic 11 Beta,15(R)-bis(5'',6''-dihydro-2H-pyran-4''-yloxy)-9 Alpha-hydroxy-13-trans-prostenoic acid.
 21. A compound according to claim 1wherein the compound is lower alkyl 9 Alpha ,11 Alpha,15(S)-tris(5'',6''-dihydro-2H-pyran-4''-yloxy)-5-cis,13-trans-prostadienoicacid.